Elsevier

Schizophrenia Research

Volume 143, Issue 1, January 2013, Pages 116-124
Schizophrenia Research

A multimodal approach to investigate biomarkers for psychosis in a clinical setting: The integrative neuroimaging studies in schizophrenia targeting for early intervention and prevention (IN-STEP) project

https://doi.org/10.1016/j.schres.2012.11.012Get rights and content

Abstract

Longitudinal clinical investigations and biological measurements have determined not only progressive brain volumetric and functional changes especially around the onset of psychosis but also the abnormality of developmental pathways based on gene–environment interaction model. However, these studies have contributed little to clinical decisions on their diagnosis and therapeutic choices because of subtle differences between patients and healthy controls. A multi-modal approach may resolve this limitation and is favorable to explore the pathophysiology of psychosis. The integrative neuroimaging studies for schizophrenia targeting early intervention and prevention (IN-STEP) is a research project aimed at exploring the pathophysiological features of the onset of psychosis and investigating possible predictive biomarkers for the clinical treatment of psychosis. Since 2008, we have adopted blood sampling, neurocognitive batteries, neurophysiological assessment, structural imaging, and functional imaging longitudinally for help-seeking ultra-high-risk (UHR) individuals and patients with first-episode psychosis (FEP). Here, we intend to introduce the IN-STEP research study protocol and present preliminary clinical findings. Thirty-seven UHR individuals and 30 patients with FEP participated in this study. Six months later, there was no difference in objective and subjective scores between the groups, which suggests that young people having symptoms and functional deficits should be cared for regardless of their history of psychosis according to their clinical stages. The rate of transition to psychosis was 7.1%, 8.0%, and 35.3% (at 6, 12, and 24 months, respectively). Through this research project, we expect to clarify the pathophysiological features around the onset of psychosis and improve the prognosis of psychosis through clinical application.

Introduction

Longitudinal clinical investigations and neuropsychological, neurophysiological, and neuroimaging measurements have helped to elucidate the pathophysiological features of schizophrenia (Insel, 2010). Recent studies have shown the abnormality of developmental pathways based on gene–environment interaction model and progressive brain volumetric and functional changes especially around the onset (Insel, 2010, van Os et al., 2010). However, these studies have contributed little to clinical decisions on their diagnosis and therapeutic choices until now (Borgwardt and Fusar-Poli, 2012). One possible problem is that most of the methods and instruments applied have substantial limitations and cannot clearly illustrate detailed and schematic brain changes, because differences between patients and healthy controls are subtle. Replication studies and more sophisticated methods are required to provide good reliability and validity prior to clinical application.

Multi-modal approaches may resolve these limitations and reveal the specific pathophysiology of psychosis (Salisbury et al., 2007, Prata et al., 2009, Takizawa et al., 2009, Fusar-Poli et al., 2010, Fusar-Poli et al., 2011b). For example, several imaging genetic studies have suggested that variations in the catechol-O-methyltransferase genotype have different effects on the frontal cortical function in patients with schizophrenia and healthy controls (Prata et al., 2009, Takizawa et al., 2009). A previous longitudinal multi-modal imaging study indicated that progressive deficits of auditory mismatch negativity (MMN) occur concurrently with progressive brain volume reduction in the temporal cortex (Salisbury et al., 2007). Longitudinal and multi-modal studies are required to elucidate the pathophysiology of psychosis, to develop biomarkers that are easy to use in clinical settings, and finally to help with patients better prognoses (Borgwardt and Fusar-Poli, 2012).

We previously reported several neurocognitive (Suga et al., 2011, Yoshida et al., 2011), neurophysiological (Kawakubo and Kasai, 2006, Kawakubo et al., 2007, Salisbury et al., 2007), and neuroimaging studies (Kasai et al., 2003a, Kasai et al., 2003b, Takizawa et al., 2008, Takizawa et al., 2009, Suga et al., 2010, Yamasaki et al., 2010, Koike et al., 2011b). However, most of the studies were cross-sectional and evaluated patients with chronic schizophrenia using a single modality. Since 2008, we have longitudinally evaluated ultra-high-risk (UHR) individuals and patients with first-episode psychosis (FEP) in a multi-modal fashion, and we already reported cross-sectional data from these studies (Koike et al., 2011b, Iwashiro et al., 2012). In this article, we introduce our research project, the Integrative Neuroimaging Studies in Schizophrenia Targeting for Early Intervention and Prevention (IN-STEP), aimed at exploring the pathophysiological features of the onset of psychosis and investigating possible predictive biomarkers for the clinical treatment of psychosis. We also introduce preliminary clinical assessments at baseline and at a 6-month follow-up until July 2012.

Section snippets

Research design

This research project was designed as a prospective observational cohort study to explore the pathophysiological features of psychosis, especially toward the onset, and to investigate possible predictive biomarkers of clinical outcome; therapeutic choice; early detection; and finally, the prediction of psychosis in clinical settings. The measurement protocol is illustrated in Table 1.

The target sample size is 100 help-seeking UHR individuals and 100 patients with FEP for the clinical

Results

In total, 159 individuals were assessed using SIPS, and 104 individuals fulfilled the UHR or FEP criteria (Fig. 1). Thirty-seven UHR individuals and 30 patients with FEP participated in this study. The number of diagnoses in the UHR individuals according to SIPS and in the FEP patients according to the DSM-IV is summarized in Table 3. At baseline, the GAF score was significantly different between the groups, but the other scores were not significantly different (Table 4).

Six months later, we

Discussion

The goal of our research project is to explore the pathophysiological features with regard to the onset of psychosis using a longitudinal and multi-modal measurement approach and to investigate the possible predictive biomarkers of clinical outcome, therapy choice, early detection, and prediction of psychosis in clinical settings. We adopted gene, biochemical agents, neurophysiological data, brain images, and clinical features as objective biomarkers (Table 1). We have already reported

Role of funding source

This study was supported by grants from the Ministry of Health, Labour, and Welfare (Health and Labour Sciences Research Grants, Research on Psychiatric and Neurological Diseases and Mental Health, H22-seishin-ippan-015 to KK; Health and Labour Science Research Grants for Comprehensive Research on Disability Health and Welfare, H23-seishin-ippan-002 to RT and YN), from Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network and Adolescent Mind &

Contributors

SK, YT, MS, SY, RT, TA, and KK designed the protocol. SK wrote the entire manuscript and undertook the statistical analysis in this article. MS and SY wrote the “Neurocognitive battery” section; YT, NI, T Natsubori, NY, and HY, the “MRI” section; T Nagai, MT, and TA, the “Event-related potential” section; and SK, YS, and YN, the “Near-infrared spectroscopy” section. SK, YT, NI, YS, T Nagai, T Natsubori, MT, MS, and SY contributed to the implementation of this project. SK, MS, SY, RT, TA, and KK

Conflict of interest

None.

Acknowledgment

We thank all the participants for voluntary cooperation in this study. We also thank Chie Shimojyo for database management.

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